Uridine diphosphate glucuronosyltransferases (UDP-glucuronosyltransferases, UGT) are enzymes that catalyze glucuronidation of various drugs. UGTs are grouped into two families, UGT1 and UGT2, based on the homology of their amino acid sequences.
At least 9 isoforms are known to exist for UGT1, that is, UGT1A1 and UGT1A3 to UGT1A10. For example, UGT1A1 conjugates bilirubin, amine, phenol and the like, while UGT1A6 conjugates phenol that has a planar molecular structure. Human UGT1 gene (UGT1) is present on the chromosome 2q37 and comprises an exon 1 that is substrate specific for each isoform (1A1 to 1A10 ) and exons 2 to 5 that are common for all isoforms, and has a promoter region including a TATA box that is present upstream of each exon 1. The isoforms have the irrespective unique amino terminal regions that are encoded by one of at least nine exons in the first exon group, and a common carboxyl terminal region that is encoded by 4 exons.
Meanwhile, UGT2 is grouped into the subfamilies of UGT2A that conjugates odorants and UGT2 that conjugates bile acids and steroids.
Jaundices for which a clear cause (observation of hemolysis etc.) is not found and which exhibit no abnormality other than a high serum bilirubin value in a standard liver function test are referred to as “constitutional jaundices” and are broadly classified into Crigler-Najjar syndrome type I and type II and Gilbert syndrome in which indirect (unconjugated type) bilirubin rises in level, and Dubin-Johnson syndrome and Rotor syndrome in which direct (conjugated type) bilirubin rises in level. It has been reported that a mutation occurs in exon 5 of UGT1A1 gene in Crigler-Najjar syndrome type I and type II and Gilbert syndrome. More specifically, due to a mutation (Y486D) in which tyrosine is replaced with aspartic acid at position 486 in the amino acid sequence, the enzyme activity drops to 1/13th that of the normal enzyme.
Meanwhile, cytochrome P450 is well known as a substance involved in drug metabolism in the body. It is also well known that due to differences in polymorphisms of this enzyme a specific drug may not be metabolized to cause abnormality in drug metabolism. Abnormalities in drug metabolism are caused not only by polymorphisms of cytochrome P450. Since a drug undergoes glucuronidation to be metabolized as described above, it has been known that polymorphisms of UGT are involved in drug metabolism. However, with respect to the relation between polymorphisms of UGT and the metabolism of various drugs, an available mutation of genes that can reflect metabolism for a large number of drugs is unclear. In particular, the relation between mutations of the exon 5 region of UGT1gene and drug metabolism is unclear.